Potential roles of intestinal microbiota in development and mitigation of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin) toxicity.

<p><i>In vivo</i>, CPT-11 is converted to the pharmacologically active SN-38 (7-ethyl-10-hydroxy-camptothecin), which is responsible for both anti-tumor activity and dose-limiting toxicity. SN-38 undergoes hepatic glucuronidation and is secreted into the bile as inactive the glucuronide SN-38G. Deconjugation of SN-38G in large intestine by bacterial β-glucuronidases intensifies the epithelial exposure to SN-38 and mediates gut toxicity <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Wallace1" target="_blank">[2]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Sparreboom1" target="_blank">[43]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Takasuna1" target="_blank">[44]</a>. APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin) and NPC (7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine) are both important CPT-11 metabolites produced by alternative hepatic detoxification mechanism, but they play little role in gastrointestinal toxicity <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Innocenti1" target="_blank">[45]</a>. The composition of intestinal microbiota was reported to be altered in colorectal cancer patients <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Wang1" target="_blank">[6]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Zwielehner1" target="_blank">[8]</a> and by various chemotherapeutic agents <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Stringer1" target="_blank">[7]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Lin1" target="_blank">[9]</a>. On the other hand, dietary fibres are known to promote the growth of beneficial bacteria in animals and human <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Raninen1" target="_blank">[46]</a>. Bacterial translocation to extraintestinal sites, was reported to be increased by CPT-11 treatment <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Stringer1" target="_blank">[7]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Brandi1" target="_blank">[47]</a> increased the risk of systemic infection. Bacterial translocation from intestine can be promoted by overgrowth of selective species in intestinal microbiota and/or a compromised host defense system, including immunodeficiency and increased intestinal permeability <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Berg1" target="_blank">[11]</a>, both of which have been reported in CPT-11-treated animals <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Stringer1" target="_blank">[7]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Nakao1" target="_blank">[48]</a>. Dietary fibres have been shown to promote intestinal health through bacterial fermentation products short-chain fatty acids (SCFA), especially butyrate. The majority of butyrate is consumed by mucosal cells. Its main functions in intestine include (1) promoting proliferation and growth of normal colonocytes, (2) enhancing epithelial barrier function, and (3) suppressing inflammation and oxidative stress <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Hamer1" target="_blank">[36]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083644#pone.0083644-Canani1" target="_blank">[42]</a> Therefore, the protective effect of butyrate may counteract injuries caused by SN-38.